Certain 3,3&#39;-[[[(2-phenyl-4-thiazolyl)methoxy]phenyl]methylene]dithiobis-propanoic acid derivatives

ABSTRACT

There are disclosed compounds of the formula ##STR1## wherein X is ##STR2## Y is ##STR3## Z is --(CH 2 ) n  O--, --(CH 2 ) n  S--, ##STR4## R 1  is ##STR5## n is 0-5; R 2  is hydrogen, loweralkyl, loweralkoxy, lower alkoxycarbonyl, trifluoromethyl, nitro, cyano or halo; 
     R 3  is ##STR6## W represents a bond or --O--, --S-- or ##STR7## m is 1-15; R 4  is hydrogen or loweralkyl; 
     R 5  is lower alkyl, monofluoroloweralkyl, difluroloweralkyl, polyfluroloweralkyl, perfluoroloweralkyl or ##STR8## R 6  is hydrogen lower alkyl, --COOR 4  or ##STR9## R 7  is OR 4  or N(R 4 ) 2  ; R 8  is OR 4  or N(R 4 ) 2  ; 
     and the pharmaceutically acceptable salts thereof, and their use in the treatment of leukotriene-mediated naso-bronchial obstruction airpassageway conditions, such as allergic rhinitis, allergic bronchial asthma and the like, as antiinflammatory agents.

This application is a continuation-in-part of U.S. Ser. No. 311,558,filed Feb. 15, 1989 now U.S. Pat. No. 4,895,953, which is a division ofU.S. Ser. No. 103,224, filed Sept. 30, 1987, now U.S. Pat. No.4,826,990.

This invention relates to novel 2-aryl substituted heterocycliccompounds possessing lipoxygenase inhibitory and leukotriene antagonistactivity, which are useful as anti-inflammatory and antiallergic agents.

It is known that arachidonic acid (AA) is metabolized in mammals by twodistinct pathways. The metabolism of arachidonic acid by cyclooxygenaseenzymes results in the production of prostaglandins and thromboxanes.The physiological activity of the prostaglandins has already been amplyelucidated in recent years. The other pathway of AA metabolism involveslipoxygenase enzymes and results in the production of a number ofoxidative products called leukotrienes. The latter are designated by theLT nomenclature system, and the most significant products of thelipoxygenase metabolic pathway are the leukotrienes B₄, C₄, D₄ and E₄.The substance denominated slow-reacting substance of anaphylaxis (SRS-A)has been shown to consist of a mixture of sulfidopeptide leukotrienes,C₄, D₄ and E₄ [see Bach et al., J. Immun., 215, 115-118 (1980); Biochem.Biophys. Res. Commun. 92, 1121-1126 (1980)].

The significance of these leukotrienes is that a great deal of evidencehas been accumulated showing that leukotrienes participate ininflammatory reactions, exhibit chemotactic activities, stimulatelysosomal enzyme release and act as important factors in the immediatehypersensitivity reaction. It has been shown that LTC₄ and LTD₄ arepotent bronchoconstrictors of the human bronchi [see Dahlen et al.,Nature, 288, 484-486 (1980) and Piper, Int. Arch. Appl. Immunol., 76,suppl. 1, 43 (1985)] which stimulate the release of mucus from airwaysin vitro [Marom et al., Am. Rev. Resp. Dis., 126, 449 (1982)], arepotent vasodilators in skin [see Bisgaard et al., Prostaglandins, 23,797 (1982)], andproduce a wheal and flare response [Camp et al., Br. J.Pharmacol., 80, 497 (1983)]. The nonpeptide leukotriene, LTB₄, is apowerful chemotactic factor for leukocytes [see A. W. Ford-Hutchinson,J. Roy. Soc. Med., 74, 831-833 (1981)], which stimulates cellaccumulation and affects vascular smooth muscle [see Bray, Br. Med.Bull., 39, 249 (1983)]. The activity of leukotrienes and mediators ofinflammation and hypersensitivity is extensively reviewed in Bailey andCasey, Ann. Reports Med. Chem., 17, 203-217 (1982) and in Bray, Agentsand Actions, 19, 87 (1986).

Accordingly, the biological activity of the leukotrienes and SRS's, andof lipoxygenase as the enzyme leading to the metabolism of AA toleukotrienes, indicates that a rational approach to drug therapy toprevent, remove or ameliorate the symptoms of allergies, anaphylaxis,asthma and inflammation must focus on either blocking the release ofmediators of these conditions or antagonizing their effects. Thus,compounds which inhibit the biological effects of the leukotrienes andSRS's and/or which control the biosynthesis of these substances, as byinhibiting lipoxygenase, are considered to be of value in treating suchconditions as allergic bronchial asthma, allergic rhinitis, as well asin other immediate hypersensitivity reactions.

The invention provides novel compounds of the formula ##STR10## whereinX is ##STR11## Y is ##STR12## Z is --(CH₂)_(n) O--, --(CH₂)_(n) S--,##STR13## R¹ is ##STR14## n is 0-5; R² is hydrogen, loweralkyl,loweralkoxy, lower alkoxycarbonyl, trifluoromethyl, nitro, cyano orhalo;

R³ is ##STR15## W represents a bond or --O--, --S-- or ##STR16## m is1-15; R⁴ is hydrogen or loweralkyl;

R⁵ is lower alkyl, monofluoroloweralkyl, difluoroloweralkyl,polyfluoroloweralkyl, perfluoroloweralkyl or ##STR17## R⁶ is hydrogen,lower alkyl, --COOR⁴ or ##STR18## R⁷ is OR⁴ or N(R⁴)₂ ; R⁸ is OR⁴ orN(R⁴)₂ ;

and the pharmaceutically acceptable salts thereof.

The term "halo" refers to fluoro, chloro, and bromo. The terms"loweralkyl" and "loweralkoxy" refer to moieties having 1-6 carbon atomsin the carbon chain.

The compounds of the invention can be prepared via variants of a basicreaction scheme using appropriate starting materials. Thus, compounds inwhich R¹ is the moiety ##STR19## can be prepared by the reaction of anappropriate aniline derivative with an appropriate alkyl sulfonylchloride or alkyl sulfonic anhydride as follows: ##STR20## where X, Y,R², R⁴, R⁵ and n are as defined hereinbefore and hal refers to a haloradical, for example, chloro or bromo. The reaction is carried out in anorganic solvent, for instance tetrahydrofuran, and at room temperature.The starting aniline derivatives employed in this reaction sequence andin which, for example Z is --CH₂ O--, can be prepared as follows:##STR21## Additionally, those compounds in which R¹ is the moiety##STR22## and R³ is lower alkyl, can be readily prepared from thecompounds wherein R⁴ is lower alkyl by the following reaction sequence:##STR23## wherein X, Y, R², R⁴, R⁵ and n are as defined hereinbefore andZ¹ is the replaceable portion of the alkylating agent R⁴ Z¹, which canbe any of the conventional alkylating agents, such as for example thealkyl halides, alkyl sulfates, alkyl sulfonates and so forth.

Compounds of the invention in which R¹ is ##STR24## and R⁴ is hydrogen,can be prepared by the following reaction scheme, where Z is again --CH₂O--: ##STR25## Those compounds in which R⁴ is lower alkyl can beprepared by alkylating the tetrazole moiety using conventionalalkylating agents, such as alkyl halides, alkyl sulfates, alkylsulfonates and so forth.

Compounds of the invention in which R¹ is ##STR26## can be prepared bythe reaction of an appropriate R-, S- or racemic phenylephrine; R-, S-or racemic norphenylephrine; R-, S- or racemic N-ethylphenylephrine; orR-, S- or racemic N-ethylnorphenylephrine derivative with an appropriatebenzo-fused heterocyclic derivative as follows: ##STR27## where X, Y,R², R⁴ and R⁶ are as defined hereinbefore and hal refers to a haloradical, for example, chloro or bromo. The reaction is carried out inthe presence of cesium carbonate in an organic solvent, for instanceacetone, under reflux conditions. The various startingphenylephrine-based derivatives employed in the reaction sequence can beprepared as follows (illustrating preparation of a phenylephrinestarting material): ##STR28##

Compounds of the invention in which R¹ is ##STR29## or --(CH₂)_(n) COOR⁴can be prepared according to two preparative schemes. For thosecompounds in which n≧2, the following representative sequence isemployed: ##STR30## The resulting compounds obtained by this sequenceare hydrolyzed to yield intermediate carboxylic acids: ##STR31## whichare then reacted with an appropriate sulfonamide reactant to yield thedesired sulfonylcarboxamide derivatives: ##STR32## or the carboxylicacid can be esterified to yield the appropriate ester: ##STR33##

For those compounds in which R¹ is ##STR34## and n is 0 or 1, thefollowing reaction sequence is employed, in which R⁴ is lower alkyl:##STR35## The resulting carboxylic acid ester compounds can then bereacted with hydrazine hydrate to yield the desired hydrazide finalcompounds: ##STR36## The latter can be further reacted in the presenceof 1,1'-carbonyldiimidazole to yield the final compounds containing theoxadiazolone grouping: ##STR37##

Alternatively, the carboxylic acid ester compounds can be hydrolyzed tothe carboxylic acids, which can then be reacted with the appropriatesulfonamide reactants in order to obtain the desired sulfonylcarboxamidederivatives: ##STR38##

Compounds of the invention in which R¹ is ##STR39## can be preparedusing the carboxylic acid ester compounds described in the immediatelypreceding reaction sequences as starting compounds: ##STR40##

Finally, compounds of the invention in which R¹ is ##STR41## can beprepared by the following reaction sequence: ##STR42##

The resulting intermediate is then utilized to prepare the desired finalcompounds via several different schemes: ##STR43##

The starting ketal in the above-outlined preparative sequence can beprepared by the reaction of a suitable 3-hydroxybenzaldehyde withethylene glycol in the presence of p-toluenesulfonic acid: ##STR44##

The 2-aryl substituted heterocyclic compounds used as starting materialin all the above reaction sequences are either commercially available orcan be prepared by methods conventional in the art. Thus, for example,such compounds as 4-(chloromethyl)-5-methyl-2-[4-(methoxy)phenyl]oxazolecan be prepared according to the method described by Goto et al., Chem.Pharm. Bull., 19, 2050 (1971); 2-phenyl-4-chloromethylthiazole by themethod described by Marzoni, J. Heterocyclic Chem., 23, 577 (1986), and2-chloromethyl-6-phenylpyridine by the method desribed in EuropeanPatent Publication No. 146,370.

Compounds of the invention which contain a basic nitrogen are capable offorming pharmacologically acceptable salts, including the salts ofpharmacologically acceptable organic and inorganic acids such ashydrochloric, hydrobromic, sulfuric, nitric, phosphoric,methanesulfonic, benzenesulfonic, acetic, citric, fumaric, maleic,succinic and the like. The compounds which are carboxylic acids or havea hydroxamic function are capable of forming alkali metal and alkalineearth carboxylates and carboxylates of pharmacologically acceptablecations derived from ammonia or a basic amine. Examples of the latterinclude but are not limited to cations such as ammonium, mono-, di-, andtrimethylammonium, mono-, di- and triethylammonium, mono-, di-, andtripropylammonium (iso and normal), ethyldimethylammonium,benzyldimethylammonium, cyclohexylammonium, benzylammonium,dibenzylammonium, piperidinium, morpholinium, pyrrolidinium,piperazinium, 1-methylpiperidinium, 4-ethylmorpholinium,1-isopropylpyrrolidinium, 1,4-dimethylpiperazinium,1-n-butyl-piperidinium, 2-methylpiperidinium,1-ethyl-2-methylpiperidinium, mono-, di- and triethanolammonium, ethyldiethanolammonium, n-butylmonoethanolammonium,tris(hydroxymethyl)methylammonium, phenylmonoethanolammonium, and thelike.

The compounds of the invention, by virtue of their ability to inhibitthe activity of lipoxygenase enzyme and to antagonize mediators arisingfrom this enzymatic pathway, are useful in the treatment of inflammatoryconditions. Accordingly, the compounds are indicated in the treatment ofsuch diseases as rheumatoid arthritis, osteoarthritis, tendonitis,bursitis and similar conditions involving inflammation. Moreover, byvirtue of their ability to inhibit the activity of lipoxygenase enzymeand by their ability to antagonize the effect of LTC₄, LTD₄ and LTE₄which are the constituents of SRS-A, they are useful for the inhibitionof symptoms induced by these leukotrienes. Accordingly, the compoundsare indicated in the prevention and treatment of those disease states inwhich LTC₄, LTD₄ and LTE₄ are causative factors, for example allergicrhinitis, allergic bronchial asthma and other leukotriene mediatednaso-bronchial obstructive air-passageway conditions, as well as inother immediate hypersensitivity reactions, such as allergicconjunctivitis. The compounds are especially valuable in the preventionand treatment of allergic bronchial asthma.

When the compounds of the invention are employed in the treatment ofallergic airways disorders and/or as antiiflammatory agents, they can beformulated into oral dosage forms such as tablets, capsules and thelike. The compounds can be administered alone or by combining them withconventional carriers, such as magnesium carbonate, magnesium stearate,talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth,methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoabutter and the like. Diluents, flavoring agents, solubilizers,lubricants, suspending agents, binders, tablet-disintegrating agents andthe like may be employed. The compounds may be encapsulated with orwithout other carriers. In all cases, the proportion of activeingredients in said compositions both solid and liquid will be at leastto impart the desired activity thereto on oral administration. Thecompounds may also be injected parenterally, in which case they are usedin the form of a sterile solution containing other solutes, for example,enough saline or glucose to make the solution isotonic. Foradministration by inhalation or insufflation, the compounds may beformulated into an aqueous or partially aqueous solution, which can thenbe utilized in the form of an aerosol.

The dosage requirements vary with the particular compositions employed,the route of administration, the severity of the symptoms presented andthe particular subject being treated. Treatment will generally beinitiated with small dosages less than the optimum dose of the compound.Thereafter the dosage is increased until the optimum effect under thecircumstances is reached. In general, the compounds of the invention aremost desirably administered at a concentration that will generallyafford effective results without causing any harmful or deleterious sideeffects, and can be administered either as a single unit dose, or ifdesired, the dosage may be divided into convenient subunits administeredat suitable times thoughout the day.

The lipoxygenase inhibitory and leukotriene antagonist effects of thecompounds of the invention may be demonstrated by standardpharmacological procedures, which are described more fully in theexamples given hereinafter.

These procedures illustrate the ability of the compounds of theinvention to inhibit the polymorphonuclear leukocyte synthesis of thelipoxygenase product 5,12-diHETE and the cyclooxygenase product TxB₂ ;the ability of the compounds to antagonize LTD₄ -induced bronchospasmmediated by exogenously administered leukotrienes; measure the in vitroLTD₄ antagonist activity of the compounds; measure the in vivo activityof the compounds as lipoxygenase inhibitors and leukotriene antagonistsof endogenous mediators of bronchospasm and measure the in vivoantiinflammatory activity of the compounds in the rat carrageenan pawedema assay.

The following examples show the preparation and pharmacological testingof compounds within the invention.

EXAMPLE 11,1,1-Trifluoro-N-[3-[[2-(4-methoxyphenyl)-5-methyl-4-oxazolyl]methoxy]phenyl]methanesulfonamideA. 2-(4-Methoxyphenyl)-5-methyl-4-[(3-nitrophenoxy)methyl]oxazole

To a solution of 7.3 g (0.031 mol) of4-(chloromethyl)-5-methyl-2-[4-(methoxyphenyl]oxazole¹ and 4.3 g (0.031mol) of 3-nitrophenol in 350 ml of acetone are added 2 g (0.037 mol) ofcesium carbonate and 0.5 g potassium iodide and the slurry is heated toreflux for 20 hours. The mixture is filtered and the solution isconcentrated in vacuo to obtain a residue. Recrystallization fromacetone gives 6.15 g (59%) of crystals, m.p. 109°-111° C. The product isused without further purifications in subsequent reactions.

B. 3-[[2-(4-Methoxyphenyl)-5-methyl-4-oxazolyl]methoxy]benzenamine

A solution of 6.0 g (0.18 mol) of2-(4-methoxyphenyl)-5-methyl-4-[(3-nitrophenoxy)methyl]oxazole and 20.0g (0.09 mol) of stannous chloride dihydrate in 150 ml of ethanol isheated to 70° C. for 20 hours. The solution is allowed to cool to roomtemperature and poured into 2 L of ice water. The mixture is madealkaline by the addition of solid sodium bicarbonate and extracted twicewith 500 ml of ethyl acetate. The combined ethyl acetate solution iswashed with 500 ml of brine, dried over anhydrous magnesium sulfate andconcentrated in vacuo to obtain a residue. Recrystallization fromether/hexane gives 3.8 g (69%) of crystals, m.p. 132°-134° C. Theproduct is used without further purification in subsequent reactions.

C.1,1,1-Trifluoro-N-[3-[[2-(4-methoxyphenyl)-5-methyl-4-oxazolyl]methoxy]phenyl]methanesulfonamide

A solution of 8.0 g (0.026 mol) of3-[[2-(4-methoxyphenyl)-5-methyl-4-oxazolyl]methoxy]benzenamine and 3.1g (0.031 mol) of triethylamine in 100 ml of methylene chloride is cooledto -78° C. A solution of 7.9 g (0.028 mol) of trifluoromethanesulfonicanhydride in 100 ml of methylene chloride is added from a droppingfunnel and the mixture is allowed to warm to room temperature. Thesolution is concentrated in vacuo and the residue is dissolved in 400 mlof ethyl acetate/400 ml of water. The ethyl acetate layer is dried overanhydrous magnesium sulfate, and concentrated to obtain 10.9 g (95%) ofcrystals. Recrystallization from acetone-hexane gives 3.8 g (35%) ofcrystals, m.p. 201°-203° C.

Analysis for: C₁₉ H₁₇ F₃ N₂ O₅ S: Calculated: C, 51.58; H, 3.87; N,6.33. Found: C, 51.61; H, 3.91; N, 6.33.

EXAMPLE 21,1,1-Trifluoro-N-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]phenyl]methanesulfonamideA. 5-Methyl-4-[(3-nitrophenoxy)methyl]-2-phenyloxazole

To a solution of 20.0 g (0.097 mol) of4-chloromethyl-5-methyl-2-phenyloxazole¹ and 13.4 g (0.096 mol) of3-nitrophenol in 500 ml of acetone are added 38.0 g (0.125 mol) ofcesium carbonate and 1 g of potassium iodide, and the slurry is heatedto reflux for 20 hours. The mixture is filtered, and concentrated invacuo to obtain a residue. Recrystallization from acetone gives a firstcrop of 13.4 g (45%) of crystals, m.p. 106°-107° C., and a second cropof 6.6 g (22%) of crystals, m.p. 107°-108° C. The product is usedwithout further purification in subsequent experiments.

B. 3-[(5-Methyl-2-phenyl-4-oxazolyl)methoxy]benzenamine

A solution of 20.0 g (0.065 mol) of5-methyl-4-[(3-nitrophenoxy)methyl]-2-phenyloxazole and 73.0 g (0.325mol) of stannous chloride dihydrate in 600 ml of ethanol is heated to70° C. for 3 hours. The solution is allowed to cool to room temperature,and poured into 2 L of ice water. The mixture is made alkaline by theaddition of solid sodium bicarbonate, and extracted twice with 500 ml ofethyl acetate. The combined ethyl acetate solution is concentrated invacuo to obtain crystals. Recrystallization from acetone gives 8.5 g(47%) of crystals, m.p. 89°-90° C., MS (CI) 281 (M+H). The product isused without further purification in subsequent reactions.

1,1,1-Trifluoro-N-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]phenyl]methanesulfonamide

A solution of 8.5 g (0.03 mol) of3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzenamine and 3.6 g (0.036mol) of triethylamine in 75 ml of methylene chloride is cooled to -78°C. A solution of 9.2 g (0.033 mol) of trifluoromethanesulfonic anhydridein 80 ml of methylene chloride is added from a dropping funnel and themixture is allowed to warm to room temperature. The solution isconcentrated in vacuo and the residue is dissolved in 400 ml of ethylacetate/400 ml of water. The ethyl acetate layer is dried over anhydrousmagnesium sulfate, filtered through Celite and concentrated to obtain10.0 g of crystals. Recrystallization from ether gives 6.6 g (52%) ofcrystals, m.p. 157°-159° C.

Analysis for: C₁₈ H₁₅ F₃ N₂ O₄ S: Calculated: C, 52.38; H, 3.67; N, 6.79. Found: C, 52.36; H, 3.66; N, 6.67.

EXAMPLE 31,1,1-Trifluoro-N-[3-[(2-phenyl-4-thiazolyl)methoxy]phenyl]methanesulfonamideA. 4-[(3-Nitrophenoxy)methyl]-2-phenylthiazole

To a solution of 6.5 g (0.046 mol) of 3-nitrophenol in 300 ml of acetoneare added 11.6 g (0.047 mol) of 2-phenyl-4-chloromethylthiazolehydrochloride², 15 g (0.046 mol) of cesium carbonate, and 0.5 g ofpotassium iodide and the slurry is heated to reflux for 20 hours. Thehot mixture is filtered and the filtrate is concentrated in vacuo toobtain 11.7 g (82%) crystalline residue. A part is recrystallized fromethyl acetate/pentane to give crystals, m.p. 112°-114° C.

Analysis for: C₁₆ H₁₂ N₂ O₃ S: Calculated: C, 61.52; H, 3.87; N, 8.87.Found: C, 61.01; H, 3.83; N, 8.87.

B. 3-[(2-phenyl-4-thiazolyl)methoxy]benzenamine

A solution of 16.0 g (0.05 mol) of4-[(3-nitrophenoxy)methyl]-2-phenylthiazole and 56.5 g (0.25 mol) ofstannous chloride dihydrate in 300 ml of absolute ethanol is heated toreflux for 20 hours. The mixture is poured into 2 L of water and madealkaline by the addition of solid sodium bicarbonate. The mixture isextracted twice with 1 L of ethyl acetate. The combined ethyl acetatelayers are washed twice with dilute aqueous sodium chloride solution,dried over anhydrous magnesium sulfate, and concentrated in vacuo toobtain 12.0 g (85%) of an oil, which solidifies. The crystals, m.p.75°-80° C., MS (CI) 283 (M+H), are used without further purification insubsequent reactions.

C.1,1,1-Trifluoro-N-[3-[(2-phenyl-4-thiazolyl)methoxy]phenyl]methanesulfonamide

A solution of 6.0 g (0.0213 mol) of3-[(2-phenyl-4-thiazolyl)methoxy]benzenamine and 2.6 g (0.025 mol) oftriethylamine in 150 ml of methylene chloride is cooled to -78° C. Asolution of 6.6 g (0.0234 mol) of trifluoromethanesulfonic anhydride in50 ml of methylene chloride is added from a dropping funnel and themixture is allowed to warm to room temperature. The solution isconcentrated in vacuo and the residue is dissolved in 300 ml of ethylacetate/300 ml of water. The layers are separated and the ethyl acetatesolution is washed with brine, dried over anhydrous magnesium sulfate,and concentrated to an oil (11 g). The oil is chromatographed with ethylacetate/hexane as eluent. Fraction 2 is concentrated to an oil (5.4 g),which is triturated with ethyl acetate/hexane, 9/1 (v/v) to obtain 4.0 g(45%) of crystals, m.p. 113°-115° C.

Analysis for: C₁₇ H₁₃ F₃ N₂ O₃ S₂ : Calculated: C, 49.27; H, 3.16; N,6.76. Found: C, 49.28; H, 3.13; N, 6.76.

EXAMPLE 41,1,1-Trifluoro-N-[2-[(2-phenyl-4-thiazolyl)methoxy]phenyl]methanesulfonamideA. 4-[(2-nitrophenoxy)methyl]-2-phenylthiazole

To a solution of 10.7 g (0.08 mol) of 2-nitrophenol in 500 ml of acetoneare added 19.0 g (0.08 mol) of 4-chloromethyl-2-phenylthiazolehydrochloride, 26.3 g (0.08 mol) of cesium carbonate, and 0.5 g ofpotassium iodide, and the slurry is heated to reflux for 20 hours. Themixture is filtered, and the filtrate is concentrated in vacuo to obtaina crystalline residue. Recrystallization from ethanol gives 16.7 g (67%)of crystals, m.p. 95° C.

Analysis for: C₁₆ H₁₂ N₂ O₃ S: Calculated: C, 61.52; H, 3.87; N, 8.97.Found: C, 61.42; H, 4.06; N, 8.88.

B. 2-[(2-phenyl-4-thiazolyl)methoxy]benzenamine

A solution of 16.0 g (0.05 mol) of4-[(2-nitrophenoxy)methyl-2-phenylthiazole and 56.5 g (0.25 mol) ofstannous chloride dihydrate in 300 ml of ethanol is refluxed for 20hours. The mixture is poured into 2 L of ice water and made alkaline bythe addition of solid sodium bicarbonate. The mixture is extracted twicewith 1 L of ethyl acetate. The combined ethyl acetate layers are washedtwice with dilute brine, dried over anhydrous magnesium sulfate, andconcentrated in vacuo to obtain 15.3 g of an oil. 8.5 Grams of the oilare subjected to high pressure liquid chromatography (ethylacetate/hexane as eluent). Fractions 18-21 are combined and concentratedto obtain 5.4 g (38%) of crystals, m.p. 60°-62° C.

Analysis for: C₁₆ H₁₄ N₂ OS: Calculated: C, 68.06; H, 5.00; N, 9.92.Found: C, 68.06; H, 4.99; N, 9.92.

C.1,1,1-Trifluoro-N-[2-[(2-phenyl-4-thiazolyl)methoxy]phenyl]methanesulfonamide

A solution of 6.3 g (0.022 mol) of2-[(2-phenyl-4-thiazolyl)methoxy]benzenamine and 3.0 g (0.03 mol) oftriethylamine in 150 ml of methylene chloride is cooled to -70° C. Asolution of 6.6 g (0.0234 mol) of trifluoromethanesulfonic anhydride in50 ml of methylene chloride is added from a dropping funnel, and themixture is allowed to warm to room temperature. The solution isconcentrated in vacuo and the residue is dissolved in 300 ml of ethylacetate/300 ml of dilute hydrochloric acid. The layers are separated andthe aqueous phase is extracted with 300 ml of ethyl acetate. Thecombined ethyl acetate solution is twice washed with dilute brine, driedover anhydrous magnesium sulfate and concentrated to an oil, which issubjected to high pressure liquid chromatography (ethyl acetate/hexaneas eluent). Fractions 7-10 are combined and concentrated to obtain 5.0 gof crystals, m.p. 122°-125° C. The crystals are triturated with ethylacetate to obtain 2.6 g (29%) of crystals, m.p. 123°-125° C.

Analysis for: C₁₇ H₁₃ F₃ N₂ O₃ S: Calculated: C, 49.27; H, 3.16; N,6.76. Found: C, 49.32; H, 3.23; N, 6.70.

EXAMPLE 5 5-[[3-(2-Phenyl-4-thiazolylmethoxy)phenyl]methyl]-1H-tetrazoleA. 3-(2-Phenyl-4-thiazolylmethoxy)benzenacetonitrile

To a solution of 14.0 g (0.105 mol) of 3-hydroxyphenylacetonitrile in500 ml of acetone were added 25.9 g (0.105 mol) of4-chloromethyl-2-phenylthiazole hydrochloride and 34.2 g (0.105 mol) ofcesium carbonate and 1 g of potassium iodide and the slurry is heated toreflux for 20 hours. The mixture is filtered and the solution isconcentrated in vacuo to obtain crystals. Recrystallization from ethylacetate gives 14.0 g (43%) crystals, m.p. 108°-110° C. The product isused without further purification in subsequent reactions.

B. 5-[[3-(2-Phenyl-4-thiazolylmethoxy)phenyl]methyl]-1H-tetrazole

To a solution of 9.0 g (0.03 mol) of3-(2-phenyl-4-thiazolylmethoxy)benzenacetonitrile in 200 ml ofdimethylformamide are added 9.5 g (0.15 mol) of sodium azide and 7.9 g(0.15 mol) of ammonium chloride, and the slurry is heated to 135° C. for72 hours. The mixture is allowed to cool to room temperature, dilutedwith 200 ml of water, and extracted four times with 200 ml of ethylacetate. The combined ethyl acetate solution is washed with brine, driedover anhydrous magnesium sulfate, and concentrated in vacuo to obtain anoil, which is subjected to high pressure liquid chromatography (ethylacetate/hexane as eluent). Fraction 2 is concentrated to obtain 3.0 g(29%) of crystals, m.p. 160°-161° C.

Analysis for: C₁₈ H₁₅ N₅ OS: Calculated: C, 61.87; H, 4.32; N, 20.05.Found: C, 61.62; H, 4.50; N, 19.98.

EXAMPLE 6N,N-Diethyl-N'-[2-hydroxy-2-[3-(2-phenyl-4-thiazolylmethoxy)phenyl]ethyl]-N-methylurea

To a solution of 14.0 g (0.053 mol) ofN,N-diethyl-N'-[2-hydroxy-2-(3-hydroxyphenyl)ethyl]-N'-methylurea in 200ml of acetone are added 13.0 g (0.053 mol) of4-chloromethyl-2-phenylthiazole hydrochloride, 13 g (0.053 mol) ofcesium carbonate and 1 g of potassium iodide, and the slurry is refluxedfor 20 hours. The mixture is poured into 500 ml of water/500 ml of ethylacetate and the layers are separated. The aqueous phase is twiceextracted with 300 ml of ethyl acetate, and the combined ethyl acetatesolution is twice washed with brine, dried over anhydrous magnesiumsulfate and concentrated in vacuo to obtain an oil, which is subjectedto high pressure liquid chromatography (ethyl acetate/hexane as eluent).Fractions 4-12 are combined and concentrated to give an oil, which isrechromatographed. Fractions 9-10 are combined and concentrated in vacuoto obtain 4.0 g (17%) of a viscous oil.

Analysis for: C₂₄ H₂₉ N₃ O₃ S: Calculated: C, 65.57; H, 6.65; N, 9.56.Found: C, 65.20; H, 6.76; N, 9.22.

EXAMPLE 71,1,1-Trifluoro-N-[3-[(2-phenyl-6-pyridinyl)methoxy]phenyl]methanesulfonamideA. 6-[(3-Nitrophenoxy)methyl]-2-phenylpyridine

To a stirred solution of 4.2 g (0.03 mol) of 3-nitrophenol in 150 ml ofacetone is added 7.5 g (0.05 mol) of 2-chloromethyl-6-phenylpyridinehydrochloride³, 10 g (0.03 mol) of cesium carbonate and 0.5 g ofpotassium iodide, and the slurry is heated to reflux for 20 hours. Thehot mixture is filtered, and the filtrate is concentrated in vacuo toobtain an oil (9.3 g). The crude product is recrystallized from ethylacetate/pentane to give a first crop (4.5 g, 49%) of crystals, m.p.77°-80° C. and a second crop (1.7 g, 19%) of crystals, m.p. 77°-81° C.

Analysis for: C₁₈ H₁₄ N₂ O₃ : Calculated: C, 70.58; H, 4.61; N, 9.15.Found: C, 70.56; H, 4.51; N, 9.19.

B. 3-[(2-Phenyl-6-pyridinyl)methoxy]benzenamine

A suspension of 6.2 g (0.02 mol) of6-[(3-nitrophenoxy)methyl]-2-phenylpyridine in a solution of 50.0 g(0.18 mol) of ferrous sulfate heptahydrate and 0.3 ml of concentratedhydrochloric acid in 100 ml of water is heated on a steambath to 90° C.Concentrated ammonium hydroxide is added in 3 increments of 10 ml over aperiod of 10 minutes. Heating is discontinued and the reaction mixtureis allowed to cool over a period of 45 minutes while vigorouslystirring. The reaction mixture is diluted with 300 ml of water/300 ml ofethyl acetate and filtered through Celite. The filter cake is extractedonce with 300 ml of ethyl acetate, and the combined ethyl acetatesolution is concentrated in vacuo to obtain an oil (4.8 g). The oil ischromatographed with ethyl acetate/hexane as eluent. Fractions 8-11 arecombined and concentrated to obtain 2.0 g (37%) of an oil, MS (CI) 277(M+ H). The product is used without further purification in subsequentreactions.

C.1,1,1-Trifluoro-N-[3-[(2-phenyl-6-pyridinyl)methoxy]phenyl]methanesulfonamide

A solution of 2.0 g (0.00725 mol) of3-[(2-phenyl-6-pyridinyl)methoxy]benzenamine and 2.0 g (0.02 mol) oftriethylamine in 150 ml of methylene chloride is cooled to -70° C. Asolution of 2.1 g (0.00745 mol) of trifluoromethanesulfonic anhydride in50 ml of methylene chloride is added from a dropping funnel and themixture is allowed to warm to room temperature. The solution isconcentrated in vacuo, and the residue is dissolved in 250 ml of ethylacetate/250 ml of acidic, dilute aqueous sodium chloride solution. Thelayers are separated and the aqueous phase is extracted with 250 ml ofethyl acetate. The combined ethyl acetate solution is washed with brine,dried over anhydrous magnesium sulfate and concentrated to obtain anoil, MS (CI) 409 (M+H), 541 (M+H for disubstituted product). Th oil isdissolved in 25 ml of methanol and stirred with 25 ml of Claisen'sAlkali for 2 hours at room temperature. The reaction mixture is dilutedwith water, acidified, and extracted twice with ethyl acetate. Thecombined ethyl acetate solution is washed with brine, dried overanhydrous magnesium sulfate to obtain an oil (0.5 g), MS (CI) 409 (M+H),which crystallizes. The crystals are triturated with ethylacetate/pentane to obtain 0.17 g (2.1%) crystals, m.p. 115°-117° C.

Analysis for: C₁₉ H₁₅ F₃ N₂ O₃ S: Calculated: C, 55.87; H, 3.70; N,6.86. Found: C, 55.79; H, 3.66; N, 6.76.

EXAMPLE 8N-[(4-Methylphenyl)sulfonyl]-3-[(2-phenyl-4-thiazolyl)methoxy]benzamideA. 3-[(2-Phenyl-4-thiazolyl)methoxy]benzoic acid

A slurry of 10.5 g (0.05 mol) of 2-phenyl-4-chloromethylthiazole, 7.6 g(0.05 mol) of methyl-3-hydroxybenzoate, 16.2 g (0.05 mol) of cesiumcarbonate, and 0.1 g of potassium iodide in 100 ml of acetone isrefluxed for 16 hours. The mixture is filtered and the solution isconcentrated in vacuo to obtain 15.5 g of oil. To 2.0 g of this oil isadded 60 ml 1N NaOH and 40 ml tetrahydrofuran and the mixture refluxed 2hours. The mixture is concentrated in vacuo to an aqueous solution. Theaqueous solution is acidified to pH 6 and filtered to get 5.5 g solids,m.p. 155°-157° C.

Analysis for: C₁₇ H₁₃ NO₃ S: Calculated: C, 65.57; H, 4.21; N, 4.50.Found: C, 65.15; H, 4.24; N, 4.10.

B.N-[(4-Methylphenyl)sulfonyl]-3-[(2-phenyl-4-thiazolyl)methoxy]benzamide

To a solution of 5.48 g (0.0176 mol) of3-[(2-phenyl-4-thiazolyl)methoxy]benzoic acid in 100 ml of toluene areadded 3.24 g (0.0200 mol) of 1,1'-carbonyldiimidazole and the solutionis stirred for 1 hour. To this solution, 3.01 g (0.0176 mol)p-toluenesulfonamide are added and the solution is refluxed for 16hours. After cooling, the bottom layer is isolated and concentrated invacuo to obtain a clear oil. The clear oil is dissolved in methylenechloride and is washed twice with pH 4 buffer solution, twice with waterand is concentrated in vacuo to obtain a residue. Recrystallization fromtoluene/ethyl acetate gives 1.5 g (18%) of crystals, m.p. 170°-172° C.

Analysis for: C₂₄ H₂₀ N₂ O₄ S₂ : Calculated: C, 62.05; H, 4.34; N, 6.03.Found: C, 62.20; H, 4.50; N, 5.87.

EXAMPLE 9

Following the procedure of Example 3 and using the appropriate2-substituted-4-chloromethylthiazole hydrochloride starting material,the following compounds are prepared:

A.1,1,1-Trifluoro-N-[3-[[2-(4-chlorophenyl)-4-thiazolyl]methoxy]phenyl]methanesulfonamide,m.p. 147°-149° C.

Analysis for: C₁₇ H₁₂ ClF₃ N₂ O₃ S₂ : Calculated: C, 45.49; H, 2.70; N,6.24. Found: C, 45.58; H, 2.91; N, 6.01.

B.1,1,1-Trifluoro-N-[3-[[2-(4-fluorophenyl)-4-thiazolyl]methoxy]phenyl]methanesulfonamide,m.p. 134°-136° C.

Analysis for: C₁₇ H₁₂ F₄ N₂ O₃ S₂ : Calculated: C, 47.22; H, 2.80; N,6.48. Found: C, 47.24; H, 2.86; N, 6.38.

C.1,1,1-Trifluoro-N-[3-[[2-(2-fluorophenyl)-4-thiazolyl]methoxy]phenyl]methanesulfonamide,m.p. 152°-154° C.

Analysis for: C₁₇ H₁₂ F₄ N₂ O₃ S₂ : Calculated: C, 47.22; H, 2.80; N,6.48. Found: C, 47.46; H, 3.12; N, 6.55.

D.1,1,1-Trifluoro-N-[3-[[2-(2,6-difluorophenyl)-4-thiazolyl]methoxy]phenyl]methanesulfonamide,m.p. 169°-172° C.

Analysis for: C₁₇ H₁₁ N₂ F₅ O₃ S₂ : Calculated: C, 45.33; H, 2.46; N,6.22. Found: C, 45.55; H, 2.65; N, 6.18.

E.1,1,1-Trifluoro-N-[3-[[2-(4-trifluoromethylphenyl)-4-thiazolyl]methoxy]phenyl]-methanesulfonamide,m.p. 144°-146° C.

Analysis for: C₁₈ H₁₂ F₆ N₂ O₃ S₂ : Calculated: C, 44.81; H, 2.51; N,5.81. Found: C, 44.89; H, 2.68; N, 5.63.

F.1,1,1-Trifluoro-N-[3-[[2-(3-trifluoromethylphenyl)-4-thiazolyl]methoxy]phenyl]methanesulfonamide,m.p. 138°-142° C.

Analysis for: C₁₈ H₁₂ F₆ N₂ O₃ S₂ : Calculated: C, 44.81; H, 2.51; N,5.81. Found: C, 44.77; H, 2.89; N, 5.84.

G.1,1,1-Trifluoro-N-[3-[[2-(2-trifluoromethylphenyl)-4-thiazolyl]methoxy]phenyl]methanesulfonamide,m.p. 109°-111° C.

Analysis for: C₁₈ H₁₂ F₆ N₂ O₃ S₂ : Calculated: C, 44.81; H, 2.51; N,5.81. Found: C, 44.89; H, 2.76; N, 5.81.

H.1,1,1-Trifluoro-N-[3-[[2-(4-methoxyphenyl)-4-thiazolyl]methoxy]phenyl]methanesulfonamide,m.p. 154°-157° C.

Analysis for: C₁₈ H₁₅ F₃ N₂ O₄ S₂ : Calculated: C, 48.64; H, 3.40; N,6.30. Found: C, 49.00; H, 3.29; N, 6.24.

I.1,1,1-Trifluoro-N-[3-[[2-(benzyl)-4-thiazolyl]methoxy]phenyl]methanesulfonamide,m.p. 146°-149° C.

Analysis for: C₁₈ H₁₅ F₃ N₂ O₃ S₂ : Calculated: C, 50.46; H, 3.53; N,6.54. Found: C, 50.31; H, 3.74; N, 6.22.

EXAMPLE 10 3-[[2-(2-Fluorophenyl)-4-thiazolyl]methoxy]benzoic acidhydrazide A. 3-[[2-(2-Fluoromethyl)-4-thiazolyl]methoxy]benzoic acidmethyl ester

A stirred mixture of 0.23 g (0.001 mol) of4-[[3-(chloromethyl)phenoxy]methyl]-2-(2-fluorophenyl)thiazole, 0.15 g(0.001 mol) of methyl-3-hydroxybenzoate and 0.32 g (0.001 mol) of cesiumcarbonate in 20 ml of acetone is heated under reflux for 3 hours. Themixture is filtered and the filtrate is evaporated in a rotaryevaporator. The residue is recrystallized from heptane to give 0.09 g ofproduct, m.p. 83°-86° C.

Analysis for: C₁₈ H₁₄ FNO₃ S: Calculated: C, 62.96; H, 4.11; N, 4.08.Found: C, 63.40; H, 4.33; N, 4.33.

B. 3-[[2-(2-Fluorophenyl)-4-thiazolyl]methoxy]benzoic acid hydrazide

A stirred mixture of 5.0 g of3-[[2-(2-fluoromethyl)-4-thiazolyl]methoxy]benzoic acid methyl ester in70 ml of methanol containing 5 ml of hydrazine hydrate is heated underreflux for 24 hours. The mixture is cooled and the insoluble material iscollected. The filter cake is recrystallized from acetonitrile to afford3.5 g of title product, m.p. 143°-145° C.

Analysis for: C₁₇ H₁₄ FN₃ O₂ S: Calculated: C, 59.46; H, 4.11; N, 12.24.Found: C, 59.52; H, 4.29; N, 12.44.

EXAMPLE 115-[3-[[2-(2-Fluorophenyl)-4-thiazolyl]methoxy]phenyl]-1,3,4-oxadiazol-2(3H)-one

A stirred mixture of 3.4 g (0.01 mol) of3-[[2-fluorophenyl)-4-thiazolyl]methoxy]benzoic acid hydrazide preparedaccording to Example 10 and 1.6 g (0.01 mol) of 1,1'-carbonyldiimidazolein 50 ml of dichloromethane is heated under reflux for 3 hours. Themixture is evaporated in a rotary evaporator and the residue isrecrystallized from ethanol to provide 2.5 g of title product, m.p.198°-202° C.

Analysis for: C₁₈ H₁₂ FN₃ O₃ S: Calculated: C, 58.53; H, 3.28; N, 11.38.Found: C, 58.79; H, 3.53; N, 11.47.

EXAMPLE 123,3'-[[3-[(2-Phenyl-4-thiazoly)methoxyphenyl]methylene]dithiobis[propanoicacid]dimethyl ester A. 4-Chloromethyl-2-phenylthiazole

A mixture of thiobenzamide (13.7 g, 0.10 mol), 1,3-dichloroacetone (12.7g, 0.10 mol), sodium bicarbonate (8.4 g, 0.10 mol) and dichloroethane(200 mL) is refluxed for 6 hours. The reaction mixture is cooled to 23°C. and the solid by-products are removed by filtration. The filtrate isconcentrated under reduced pressure to give the crude product (19.0 g).This material is recrystallized from hexane and the title product isobtained as a light yellow solid (18.2 g) in 86.0% yield, m.p. 44°-48°C.

B. 4-[3-(1,3-Dioxolan-2-yl)phenoxy]methyl]-2-phenylthiazole

A mixture of 4-chloromethyl-2-phenylthiazole (13.7 g, 0.0653 mol),1-(1,3-dioxolan-2-yl)-3-hydroxybenzene (13.6 g, 0.0817 mol (25%excess)), cesium carbonate (26.7 g, 0.082 mol) and dimethylsulfoxide (70mL) is heated at 45° to 50° C. for 2 hours. The reaction mixture isslowly poured into ice water (500 mL). The aqueous dimethyl sulfoxidesolution is extracted three times with ether (600 mL). The combinedether solution is washed with 0.5N NaOH (500 mL), brine (twice, 500 mL)and dried over MgSO₄ and silica gel (10 g). The solids are filtered andthe filtrate is concentrated under reduced pressure to a volume of ca.400 mL. The product crystallizes from the ether solution and afterfiltration, is obtained as a light yellow solid (13.0 g). Upon furtherconcentration of the filtrate, an additional 6 g of product is isolated,m.p. 77°-79° C.

¹ H NMR (CDCl₃): δ 8.0-7.0 (m, 10H), 5.8 (s, 1H), 5.3 (s, 2H), 4.15-4.0(m, 4H).

IR (KBr): 1610 cm⁻¹.

Analysis for: C₁₉ H₁₇ NO₃ S: Calculated: C, 67.24; H, 5.05; N, 4.13.Found: C, 67.34; H, 5.07; N, 4.17.

C.3,3'-[[3-[(2-Phenyl-4-thiazolyl)methoxyphenyl]methylene]dithiobis[propanoicacid]dimethyl ester

A mixture of the acetal (3.4 g, 0.010 mol) of Step B, methylmercaptopropionate (2.7 g, 0.022 mol) and methylene chloride (20 mL) iscooled to 0° C. and a solution containing BF₃.Et₂ O (3.7 mL, 0.030 mol)and methylene chloride (10 mL) is added slowly. After the addition ofthe BF₃.Et₂ O-CH₂ Cl₂ solution, the reaction mixture is stirred for 2hours at 0° C. The reaction mixture is washed with 5% NaHCO₃ (25 mL) anddried over MgSO₄. After filtration of the MgSO₄, the filtrate isconcentrated under reduced pressure to afford the crude product (5.6 g).After purification by chromatography (silica gel--30% ethyl acetate inhexane), the pure title product is obtained as a viscous yellow oil (4.0g).

¹ H NMR (CDCl₃): δ 8.0-6.9 (m, 10H), 5.30 (s, 2H), 4.96 (s, 1H), 3.67(s, 6H), 2.90-2.73 (m, 4H), and 2.60-2.54 (m, 4H).

IR (neat) 1740 cm⁻¹.

Analysis for: C₂₅ H₂₇ NO₅ S₃ : Calculated: C, 58.00; H, 5.26; N, 2.71.Found: C, 57.83; H, 5.01; N, 2.66.

EXAMPLE 133-[[[[3-(Dimethylamino)-3-oxopropyl]thio][[(2-phenyl-4-thiazolyl)methoxy]phenyl]methyl]thio]propanoicacid methyl ester

A mixture of the acetal (1.5 g, 0.004 mol) of Example 12B,N,N-dimethyl-3-mercaptopropanamide (0.65 g, 0.004 mol), methyl3-mercaptopropionate (0.59 g, 0.004 mol) and methylene chloride (15 mL)is cooled to 0° C. and a solution containing BF₃.Et₂ O (1.8 mL, 0.014mol) and methylene chloride (10 mL) is added slowly. After the additionof the BF₃.Et₂ O-CH₂ Cl₂ solution, the reaction mixture is stirred for 2hours at 0° C. The reaction mixture is diluted with an additional amountof methylene chloride (50 mL) and washed with 5% NaHCO₃ (25 mL), water(25 mL), brine (50 mL) and dried over MgSO₄. After filtration of theMgSO₄, the filtrate is concentrated under reduced pressure to afford acrude reaction mixture (2.0 g) containing three products. Separation andpurification of the three reaction products is accomplished bychromatograph (silica gel--initially ethyl acetate, then 10% methylalcohol in ethyl acetate).

The first product isolated is the diester of Example 12, wherein can befound its complete characterization.

The second product obtained is the title compound. This compound isobtained as a light yellow viscous oil (0.50 g).

¹ H NMR (DMSO-d₆) δ 8.0-7.0 (m, 10H), 5.22 (s, 3H), 3.57 (s, 3H), 2.87(s, 3H), 2.77 (s, 3H), 2.78-2.54 (m, 8H).

IR (neat): 1740 and 1650 cm⁻¹.

Mass: m/e 531 (M+H), 411, 398, 174.

Analysis for: C₂₆ H₃₀ N₂ O₄ S₃ : Calculated: C, 58.84; H, 5.70; N, 5.28.Found: C, 58.81; H, 5.61; N, 5.27.

EXAMPLE 143,3'-[[[3-[(2-Phenyl-4-thiazolyl)methoxy]phenyl]methylene]dithio]bis[N,N-dimethylpropanamide]

The title compound is isolated as the third product from the reactionmixture described in Example 13. This material is obtained as a viscousyellow oil (0.3 g).

¹ H NMR (DMSO-d₆): δ 7.96-7.04 (m, 10H), 5.22 (s, 3H), 2.87 (s, 6H),2.77 (s, 6H), 2.77-2.49 (m, 8H).

IR (CHCl₃): 1635 cm⁻¹.

MASS m/e: 544 (M+H), 411, 174. Analysis for: C₂₇ H₃₃ N₃ O₃ S₃ :Calculated: C, 59.64; H, 6.12; N, 7.73. Found: C, 59.48; H, 6.23; N,7.66.

EXAMPLE 153,3'-[[3-[(2-Phenyl-4-thiazolyl)methoxy]phenyl]methylene]dithiobis[propanoicacid]

A mixture of the diester (1.04 g, 0.002 mol) of Example 12,tetrahydrofuran (15 mL) and 2.5N NaOH (4 mL, 0.010 mol) is refluxed for4 hours. The reaction mixture is cooled and concentrated under reducedpressure. The residue is diluted with water (20 mL), and washed twicewith ether (50 mL). The aqueous layer is acidified with 1N HCl to a pHof 1 to 2 and extracted three times with ether (50 mL). The combinedether solution is washed with water (50 mL), brine (50 mL) and driedover MgSO₄. After filtration of the MgSO₄, the filtrate is concentratedunder reduced pressure to give the crude diacid product (0.8 g). Thismaterial is crystallized from ethyl acetate-petroleum ether (30°-60° C.)to afford pure title compound in 40% yield (0.40 g), m.p. 82°-84° C.(dec.).

¹ H NMR (DMSO-d₆): δ 12.27 (s, 2H0, 7.96-7.01 (m, 10H), 5.21 (s, 3H),2.70 (m, 2H), 2.60 (m, 2H), 2.47 (m, 4H).

IR (KBr): 3100 and 1705 cm⁻¹.

MASS m/e (FAB): 490 (M+H), 384, 312, 174.

Analysis for: C₂₃ H₂₃ NO₅ S₃ : Calculated: C, 56.42; H, 4.73; N, 2.86.Found: C, 56.30; H, 4.74; N, 2.82.

EXAMPLE 163-[[[[3-(Dimethylamino)-3-oxopropyl]thio][3-[(2-phenyl-4-thiazolyl)methoxy]phenyl]methyl]thio]propanoicacid

A mixture of the ester-amide (2.6 g, 0.005 mol) of Example 13, methanol(60 mL), water (5 mL), and lithium hydroxide (0.5 g, 0.012 mol) isrefluxed for 2 hours. The reaction mixture is cooled and concentratedunder reduced pressure. The residue is diluted with water (50 mL),acidified with 1N HCl to a pH of 1 to 2, and extracted three times withethyl acetate (200 mL). The combined ethyl acetate solution is washedwith water (100 mL), brine (100 mL), and dried over MgSO₄. Afterfiltration of the MgSO₄, the filtrate is concentrated under reducedpressure to give the crude acid-amide product (2.0 g). This material ispurified by chromatography (1% H₃ PO₄ washed silica gel--10% hexane inethyl acetate) and crystallized from ethyl acetate to give pure titlecompound, 0.4 g; m.p. 134°-136° C.

¹ H NMR (DMSO-d₆): δ 12.20 (s, 1H), 7.96-6.99 (m, 10H), 5.22 (s, 3H),2.87 (s, 3H), 2.77 (s, 3H), 2.70-2.49 (m, 8H).

IR (KBr): 3100, 1720 and 1600 cm⁻¹.

MASS m/e: 516 (M⁺), 384, 237, 174.

Analysis for: C₂₅ H₂₈ N₂ O₄ S₃ : Calculated: C, 58.11; H, 5.46; N, 5.42.Found: C, 58.21; H, 5.60; N, 5.39.

EXAMPLE 17

The compounds 5- and 12-hydroxyeicosatetraenoic acid (5-HETE and12-HETE) and 5, 12-dihydroxyeicosatetraenoic acid (5, 12-diHETE) areearly arachidonic acid oxidation products in the lipoxygenase cascade,which have been shown to mediate several aspects of inflammatory andallergic response. This is especially true with respect to 5,12-diHETE,which is also denoted as LTB₄ [see Ford-Hitchinson, J. Roy. Soc. Med.,74, 831 (1981)]. The assay of this Example measures the ability of thecompounds of the invention to inhibit the synthesis of 5,12-diHETE byrat glycogen-elicited polymorphonuclear leukocytes.

The assay is carried out as follows:

Peritoneal PMN are obtained from female Wistar rats (150-250 g) thatreceived an i.p. injection of 6% glycogen (10 ml). After 24 hours, ratsare killed by CO₂ asphyxiation and peritoneal cells are harvested byperitoneal lavage using Ca⁺⁺ and Mg⁺⁺ free Hanks' balanced salt solution(HBSS). The peritoneal exudate is centrifuged at 400 g for 10 minutes.After centrifugation, the lavaged fluid is removed and the cell pelletis resuspended in HBSS containing Ca⁺⁺ and Mg⁺⁺ and 10 mM L-cysteine ata concentration of 2×10⁷ cells/ml. To 1 ml portions of cell suspension,test drugs or vehicle are added and incubated at 37° C. for 10 minutes.Following this preincubation, the calcium ionophore (10 μM), A23187, isadded together with 0.5 μCi [¹⁴ C] arachidonic acid and furtherincubated for 10 minutes. The reaction is stopped by the addition of icecold water (3 ml) and acidification to pH 3.5. Lipoxygenase products arethen extracted twice into diethyl ether. The pooled ether extracts areevaporated to dryness under nitrogen and the residue is redissolved in asmall volume of methanol and spotted on aluminum backed pre-coated thinlayer chromatographic plates. The samples are then co-chromatographedwith authentic reference 5,12-diHETE in the solventsystem-hexane:ether:acetic acid (50:50:3). After chromatography, theareas associated with 5,12-diHETE standard are identified byautoradiography, cut out and quantitated by liquid scintillation.

Results are expressed as the 50% Inhibitory concentration, or as percentinhibition at a given.

Testing compounds of the invention in this assay gives the followingresults:

                  TABLE I                                                         ______________________________________                                        Compound of  50% Inhibitory Concentration                                     Example Number                                                                             (IC.sub.50) μm                                                ______________________________________                                        3            3.2                                                              8            55% at 10 μM                                                  9A           5.2                                                              9B           64% at 10 μM                                                  ______________________________________                                    

The results show that compounds of this invention have significantactivity in inhibiting the synthesis of the arachidonic acidlipoxygenase oxidation product 5,12-diHETE.

EXAMPLE 18

The procedure of Example 17 is also employed for the determination ofthe ability of the compounds of the invention to inhibit the synthesisof the arachidonic acid cyclooxygenase oxidation product TxB₂.

In this assay, the procedure of Example 17 is carried out as described.However, in order to determine cyclooxygenase activity, the samples arecochromatographed with authentic reference TxB₂ in the solvent systemethyl acetate:formic acid (80:1) and the upper phase of ethylacetate:isoctane:acetic acid:water (110:50:20:100). Afterchromatography, the areas associated with TxB₂ standard are identifiedby autoradiography, cut out and quantitated by liquid scintillationtechniques.

The results are calculated as in Example 12 and presented below:

                  TABLE II                                                        ______________________________________                                        Compound of  50% Inhibitory Concentration                                     Example Number                                                                             (IC.sub.50) μM                                                ______________________________________                                        3            1.7                                                              8            44% at 10 μM                                                  9A           7.1                                                              9B           32% at 10 μM                                                  ______________________________________                                    

The results show that the compounds tested have significant activity ininhibiting the synthesis of the arachidonic acid cyclooxygenaseoxidation product TxB₂.

EXAMPLE 19

The assay of this Example measures the in vivo ability of the compoundsof the invention to inhibit the bronchospasm induced in guinea pigs bythe exogenously administered leukotrienes C₄ and/or D₄. This assay isessentially a measure of the SRS-A antagonist properties of thecompounds tested.

This assay is carried out as follows:

Male Hartley strain guinea pigs (350-600 g) are anesthetized withpentobarbital sodium (50 mg/kg, i.p.). The jugular vein is cannulatedfor injection of drugs and the carotid artery for monitoring bloodpressure. The trachea is cannulated for artificial ventilation by aminiature Starling pump and for indirect measurement of respiratoryvolume changes as described infra. Additional pentobarbital sodium (15mg/kg, i.v.) is administered to arrest spontaneous respiration.Submaximal bronchoconstrictor responses are established in controlanimals by varying the dose-levels of leukotriene. Intravenousdose-levels for LTC₄ range from 1 to 2 μg/kg and for LTD₄ the range isfrom 0.3 to 1 μg/kg. The aerosol bronchoprovocation dose for LTC₄ isgenerated from 1.6 μM solution and for LTD₄ from a 2.0 μM solution.

Test drugs are administered either intravenously, intragastrically, byaerosol or orally at 1 or 10 minutes before induction of bronchospasm byadministration of either LTC₄ or LTD₄ at the predetermined dose-levels.Aerosols of soluble drugs or leukotrienes are produced in-line for 10seconds only by actuation of an ultrasonic nebulizer (Monaghan).Aerosolized drug dosage is expressed in terms of solution concentrationand by a fixed aerosol exposure time (approximately 10 seconds). Controlanimals receive saline in place of drug.

Respiratory volume changes are determined by a calibrated piston whosetravel is recorded, via a linear transducer, on a Beckman Dynographrecorder. Maximal bronchoconstrictor volume is determined by clampingoff the trachea at the end of the experiment. Overflow volumes at 1, 3and 5 minutes are obtained from the recorded charts.

Area under the volume overflow curve (AUC) is estimated, using theoverflow values at 1, 3 and 5 minutes, and expressed as a percentage ofthe maximal overflow AUC (equation 1): ##EQU1## Drug effects arereported as percent inhibition of % max AUC values obtained fromappropriate control animals (equation 2): ##EQU2##

Student's t-test for unpaired data is used to determine statisticalsignificance (p<0.05). ED₅₀ values can also be determined by inverseprediction from linear regression lines through points between 10 and90% inhibition.

The results for a compound of the invention are as follows:

                  TABLE III                                                       ______________________________________                                        Compound administered at 10 minutes before                                    induction of bronchospasm                                                     Compound of                                                                              Dose                   ED.sub.50                                   Example Number                                                                           (mg/kg)     % Inhibition                                                                             (mg/kg)                                     ______________________________________                                        1          25*         24                                                     2          25*         56                                                     3                                 2.4**                                                                         3.0**                                       4          25*         10                                                     5          25*         69                                                     6          25*         47                                                     7          25*         68                                                     8          25*         62                                                        9A      25*         54                                                        9B      25*         100                                                                10**       92                                                        9C      25*         73                                                                 10**       89                                                      .sup. 9D  25*         72                                                        9F      25*         50                                                       9I       25*         94                                                                 25**       47                                                     ______________________________________                                         * = intraduodenally administered                                              ** = intragastrically administered                                       

The results show that compounds of the invention have in vivo activityagainst LTD₄ induced bronchoconstriction.

EXAMPLE 20

The assay of this Example measures the in vivo ability of the compoundsof the invention to inhibit the bronchospasm induced in guinea pigs byendogenous mediators of the bronchoconstriction.

The assay is carried out as follows:

Male Hartley strain guinea pigs weighing 250-350 g are sensitized tochicken ovalbumin (OA) (10 mg i.p.) on days 1 and 3 and used starting onday 26. The animals are anesthetized with pentobarbital sodium (50mg/kg, i.p.), bilateral vagotomy is performed, and the jugular vein iscannulated for injection of drugs and the carotid artery for monitoringblood pressure. The trachea is cannulated for artificial ventilation byminiature Starling pump and for indirect measurement of respiratoryvolume changes as described, infra. Succinylcholine (2 mg/kg, i.v.) isadministered to arrest spontaneous respiration. A cyclooxygenaseinhibitor, indomethacin (10 mg/kg in tris buffer, i.v. at 9 min.) isadministered to shunt arachidonic metabolism to lipoxygenase pathways.One minute later, chlorpheniramine (1.0 mg/kg in saline, i.v.) is givento attenuate the histaminic component of anaphylacticbronchoconstriction. Test drugs (dissolved in propylene glycol,polyethylene glycol or saline) are administered either intraduodenally,intragastrically or by aerosol at 2 or 10 minutes before antigenchallenge. Anaphylactic bronchoconstriction is induced by administrationby breaths of aerosolized OA (1%) or by intravenous administration of0.1-0.3 mg/kg OA in saline. Control animals receive solvent (2 ml/kgi.d. or appropriate aerosol) in place of drug.

Respiratory volume changes are determined by a calibrated piston whosetravel is recorded, via a linear transducer, on a Beckman Dynographrecorder. Maximal bronchoconstrictor volume is determined by clampingoff the trachea at the end of the experiment. Overflow volumes atminutes 1, 3 and 5 are obtained from the recorded charts.

Area under the volume overflow curve (AUC) is estimated, using theoverflow values at 1, 3 and 5 minutes, and expressed as a percentage ofthe maximal overflow AUC (equation 1): ##EQU3## Drug effects arereported as percent inhibition of % max AUC values obtained fromappropriate control animals (equation 2): ##EQU4## Students t-test forunpaired data is used to determine statistical significance. Doseresponse curves are generated and ED₅₀ doses are interpolated from theregression lines.

The results for a compound of the invention in this assay, using LTD₄for induction of bronchospasm, are given below:

                  TABLE IV                                                        ______________________________________                                        Compound administered at 10 minutes before                                    intravenously administered ovalbumin challenge                                Compound of Example Number                                                                       Dose mg/kg % Inhibition                                    ______________________________________                                        3 .sup.            10*        81                                                                 25**       10                                              9B                 10**       22                                              9C                 10**       60                                              ______________________________________                                         * = intraduodenally administered                                              ** = intragastrically administered                                       

The results show that the compounds tested have moderate to significantin vivo activity in inhibiting ovalbumin induced bronchospasm mediatedby endogenous products of the lipoxygenase oxidation of arachidonicacid.

EXAMPLE 21

The compounds of the invention are tested in the rat carrageenan pawedema assay to determine their ability to inhibit the acute inflammatoryresponse.

This assay is carried out as follows:

140-180 gm male Sprague-Dawley rats, in groups of 6 animals, areinjected subcutaneously in the right paw with 0.1 ml of 1% carrageenanat zero time. Mercury plethysmographic readings (ml) of the paw are madeat zero time and 3 hours later. Test compounds are suspended ordissolved in 0.5% methylcellulose and given perorally 1 hour prior tocarrageenan administration.

The increase in paw volume (edema in ml.) produced by the carrageenan ismeasured. Paw edema is calculated (3 hour volume minus zero timevolume), and percent inhibition of edema is determined. UnpairedStudent's t-test is used to determine statistical significance.

The activity of standard drugs in this assay is as follows:

    ______________________________________                                        Drug         Oral ED.sub.50 (95% C.L.) mg/kg                                  ______________________________________                                        Indomethacin 3.7         (0.6, 23.8)                                          Aspirin      145.4       (33.1, 645.6)                                        Phenylbutazone                                                                             26.2        (2.3, 291.0)                                         ______________________________________                                    

When tested in this assay, the compounds of the invention gave thefollowing results:

    ______________________________________                                        Compound of   % Inhibition at                                                 Example No.   50 mg/kg (peroral)                                              ______________________________________                                        1 .sup.       34                                                              2 .sup.       18                                                              3 .sup.       51                                                              6 .sup.       57                                                              8 .sup.       51                                                              9A            60                                                              9B            55                                                              9C            53                                                              9D            37                                                              9E            66                                                              9F            23                                                              9I            22                                                              ______________________________________                                    

The results show that the compounds tested have activity in the ratcarrageenan paw edema assay, evidencing an effect on the acuteinflammatory response.

EXAMPLE 22

The compounds of the invention are tested in the isolated guinea pigtrachea assay to assess their LTD₄ antagonist activity.

The assay is carried out as follows:

Male Hartley guinea pigs (350-400 g) are euthanized by a blow to thehead, the neck is opened and the trachea removed. The trachea ismaintained in aerated physiological salt solution, cleared of connectivetissue and fat and cut into rings approximately 2 mm in width (usuallycontaining two cartilaginous segments per ring). Two pieces of silksuture are then passed through the lumen of the tracheal ring and aretied around the cartilage, one on each side of the trachealis muscle.The tracheal ring is suspended between a glass hook and a forcedisplacement transducer in a 10 ml organ bath for measurement ofisometric tension. Tissues are maintained at 37° C. in aerated (95% O₂/5% CO₂) physiological salt solution of the following composition: NaCl(118 mM), KH₂ PO₄ (1.18 mM), KCl (4.74 mM), CaCl₂ (2.5 mM), MgSO₄.7H₂ O(1.19 mM), NaHCO₃ (25 mM), Dextrose (11.1 mM) and Indomethacin (1 μM).The tracheal rings are maintained at 2 g resting tension andequilibrated for 45 minutes (with frequent washing and readjustment ofresting tension).

The tracheal rings are first contracted by the addition of carbachol(3×10⁻⁶ M), to determine tissue responsiveness and establish a referencecontraction. On attainment of a stable level of contraction(approximately 30 minutes), the tissues are washed several times untilbaseline tension has been restored and then re-equilibrated for 30minutes. The tissues are then incubated for 45 minutes with a testantagonist (either 1×10⁻⁶ M or 1×10⁻⁵ M) or 10 μl of an appropriatesolvent control (control, non-treated). One tissue in each group servesas the control. Twenty minutes prior to the construction of the LTD₄cumulative concentration-response curve, L-cysteine (1×10⁻² M final bathconcentration) is added to inhibit bioconversion of LTD₄ to LTE₄. Onlyone LTD₄ concentration-response curve is constructed in each tissue.

All responses to LTD₄ are calculated as a percentage of the referencecontraction to carbachol. LTD₄ antagonist activity is determined bycomparison of the concentration response curves of LTD₄ in the presenceand absence of antagonist. Assessment of the relative rightward shift ofthe antagonist treated curve relative to the solvent (control) treatedtissue is calculated as a concentration ratio (Eq. A) and used insubsequent calculations to derive an antagonist pK_(B) value (Eqs B&C).In the event that the maximum response to LTD₄ is depressed, the EC₅₀for that particular curve is determined, an "apparent" pK_(B) reported,and the compound reported as "not-competitive."

    ______________________________________                                         ##STR45##                                                                     ##STR46##                                                                    c) -log K.sub.B = pK.sub.B                                                    REFERENCE COMPOUNDS:                                                          Compound     pK.sub.B  pK.sub.B (Reference)                                   ______________________________________                                        WY-48,252    7.44 ± 0.12                                                                          7.70 (1)                                               LY-171,883   6.90 ± 0.23                                                                          6.65 (1)                                               ______________________________________                                    

When tested in this assay, compounds of the invention gave the followingresults:

    ______________________________________                                        Compound of     Concentration                                                 Example No.     (M)         pK.sub.B ± S.E.                                ______________________________________                                        Wy-48,252 (reference)                                                                         1 × 10.sup.-6                                                                       7.08 ± 0.04                                    12              1 × 10.sup.-5                                                                       6.14 ± 0.17                                    13              1 × 10.sup.-6                                                                       7.35 ± 0.10                                    14              1 × 10.sup.-6                                                                       6.49 ± 0.10                                    15              1 × 10.sup.-5                                                                       6.04 ± 0.06                                    16              1 × 10.sup.-6                                                                       7.14 ± 0.06                                    ______________________________________                                    

The results show the compounds tested to be competitive antagonists ofLTD₄, and that several of the compounds have activity equivalent to thatof the known highly active leukotriene antagonist, Wy-48,252.

What is claimed is:
 1. A compound having the formula ##STR47## whereinR¹ is ##STR48## R² is hydrogen, loweralkyl, loweralkoxy,loweralkoxycarbonyl, trifluoromethyl, nitro, cyano or halo;R⁴ ishydrogen or loweralkyl; R⁷ is OR⁴ or N(R⁴)₂ ; R⁸ is OR⁴ or N(R⁴)₂ ;andthe pharmaceutically acceptable salts thereof.
 2. The compound of claim1, which is3,3'-[[3-[(2-phenyl-4-thiazolyl)methoxyphenyl]methylene]dithiobis[propanoicacid]dimethyl ester.
 3. The compound of claim 1, which is3-[[[[3-(dimethylamino)-3-oxopropyl]thio][[(2-phenyl-4-thiazolyl)-methoxy]phenyl]methyl]thio]propanoicacid methyl ester.
 4. The compound of claim 1, which is3,3'-[[[3-[(2-phenyl-4-thiazolyl)methoxy]phenyl]methylene]dithio]bis[N,N-dimethylpropanamide].5. The compound of claim 1, which is3,3'-[[3-[(2-phenyl-4-thiazolyl)methoxy]phenyl]methylene]dithiobis[propanoicacid].
 6. The compound of claim 1, which is3-[[[[3-(dimethylamino)-3-oxopropyl]thio][3-[(2-phenyl-4-thiazolyl)methoxy]phenyl]methyl]thio]propanoicacid.